Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

Abstract

Severe malarial anemia (SMA) is a leading cause of mortality among children in sub-Saharan Africa. Although the novel cytokine, interleukin (IL)-23, promotes anemia in chronic inflammatory diseases, the role of IL-23 in SMA remains undefined. Since IL-23 and IL-12 share the IL-12p40 subunit and IL-12Rβ1 receptor, and are down-regulated by IL-10, relationships among these cytokines were explored in Kenyan children with varying severities of malarial anemia. Children with malarial anemia had increased circulating IL-23 and IL-10, and decreased IL-12 relative to healthy controls. Enhanced anemia severity and elevated parasitemia were associated with increased IL-10 relative to IL-23 and IL-12. Further exploration of the relationships among the cytokines using an in vitro model in which peripheral blood mononuclear cells were treated with synthetic hemozoin (sHz, malarial pigment) revealed that IL-12p35 and IL-23p19 transcripts had a sustained induction over 72 hrs, while IL-12p40 and IL-10 message peaked at 24 hrs, and rapidly declined thereafter. Taken together, results here show that IL-23 is elevated in children with malarial anemia, and that IL-10 and IL-12 appear to have important regulatory effects on IL-23 production during childhood malaria.

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

“…This mode of protection is quite novel in the IL-23/IL-17 axis of inflammation. As human malaria parasites also induce IL-23 [45], our findings provide insight into the immune mechanisms that are important to take into account malaria vaccine development or therapeutic strategies based upon IL-23.…”

IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso

“…11 There is a growing body of evidence for a key role of IL-12 in the immune response directed against Plasmodium species, whereas IL-23 was only recently proposed to be involved in malaria. 12 Neutralization of endogenous IL-12 with anti-IL-12p40 and anti-IL-12p35 antibodies in P. chabaudiinfected mice resulted in an increase of parasitemia, 13 whereas administration of recombinant IL-12 in mice and monkeys conferred a protection from Plasmodium species infection. 13,14 Studies with IL-12p40-deficient mice confirmed the effect of IL-12 in the protection against P. chabaudi.…”

Identification of Inflammatory Biomarkers for Pediatric Malarial Anemia Severity Using Novel Statistical Methods

“…Anti-inflammatory cytokines also play an important role in malarial pathogenesis through their ability to modulate the proinflammatory response. For example, IL-10 levels increase progressively with enhancing severity of childhood malarial anemia and parasite density (38) and are associated with an inability to clear malaria parasitemia (15). Increased circulating levels of IL-1 receptor antagonist (IL-1Ra) are also associated with enhanced malaria disease severity in African children (17,20), while reduced production of other anti-in-flammatory cytokines, such as transforming growth factor beta (TGF-␤), correlate with severe malaria (41).…”

“…Elevated levels of proinflammatory cytokines, including interleukin 1␤ (IL-1␤), IL-6, IL-8, IL-23, gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣), are associated with enhanced disease severity in human malaria (17,22,27,38). Conversely, decreased levels of additional proinflammatory cytokines, such as IL-12 and IFN-␣, are associated with enhanced malaria pathogenesis in humans (22,26,38,41). Anti-inflammatory cytokines also play an important role in malarial pathogenesis through their ability to modulate the proinflammatory response.…”